This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DNA ligase III is one of three human DNA ligases responsible for repairing breaks in the backbone of DNA, which if left unrepaired can lead to genomic instability, cancer and aging. We are focused on understanding how the activity of the three DNA ligases is coordinated within the cell. All three DNA ligases share the same catalytic mechanism but achieve biological specialization through protein-protein interactions and different substrate selectivity. To understand the substrate interactions of DNA ligase III, we have determined the structure of DNA ligase III in complex with nicked DNA. This structure will help define the mechanism of substrate selection by mammalian DNA ligase III in DNA damage responses.